• neurodegenerative disease

This report describes a model that postulates impact upon a common pathway for a number of phenotypically similar diseases. One of these specific diseases has been modeled in Drosophila; see ‘neurodegeneration with brain iron accumulation 1’ (FBhh0000229). It is suggested that CoA‐dependent activation of mitochondrial acyl carrier protein (NDUFAB1, also known as mtACP) plays a key role the common pathway. The protein encoded by NDUFAB1 is an accessory and non-catalytic subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). CoA transferases typically act as ‘reusable’ carrier molecules: they are not consumed during these reactions. However, the reaction required to activate NDUFAB1 does consume CoA; thus it is postulated that this reaction might be uniquely sensitive to reduced levels of CoA.

There is a single ortholog of NDUFAB1 in Drosophila, ND-ACP, for which loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. The human NDUFAB1 gene has not been introduced into flies.

Using Drosophila and Drosophila S2 cells it was shown that impairment of CoA biosynthesis leads to decreased levels of the activated form of ND-ACP, which in turn results in reduced activity of pyruvate dehydrogenase (PDH). Pharmaceuticals that enhance PDH activity were tested using a fly model of neurodegeneration with brain iron accumulation 1 (FBhh0000229) and found to rescue the reduced viability phenotype.

A wing phenotype assay has been developed to allow rapid identification of additional genes that impact the CoA‐mtACP‐PDH pathway.

[updated Aug. 2020 by FlyBase; FBrf0222196]